Autoimmunity
Abstract
Fibroblasts are central to pathogenesis of systemic sclerosis (SSc). However, studies of conventional explant fibroblast cultures incompletely reflect disease biology and treatment response. We isolated a second non-migratory “resident” population of fibroblasts from skin biopsies after outgrowth of explant “migratory” cells. These non-motile resident fibroblasts were compared with migratory cells from the same biopsy, using functional studies, bulk and scRNAseq, and localised in situ by multichannel immunofluorescence. Migratory and resident fibroblast populations in SSc showed distinct pro-fibrotic characteristics and gene expression for pathogenic pathways differing by stage and autoantibody subgroup. TGFβ signalling was highly active in migratory fibroblasts in early stage dcSSc. Conversely, resident fibroblasts had less upregulated TGFβ signalling, especially in late dcSSc. Increased chemokine expression was a hallmark of resident fibroblasts at all stages. In vitro studies confirmed differential response to TGFβ1 and CCL2 between migratory and resident cells. We suggest that migratory fibroblasts are especially important in early skin disease whereas non-migratory fibroblasts may have a regulatory role and contribute more to fibrosis in later stage disease. Thus, we have identified a pathogenic fibroblast population in SSc, not isolated by conventional explant culture, that could play an important role in fibrosis and be targeted therapeutically.
Authors
Kristina E.N. Clark, Shiwen Xu, Moustafa Attar, Voon H. Ong, Christopher D. Buckley, Christopher P. Denton
Abstract
Lipid metabolism is closely linked with antitumor immunity and autoimmune disorders. However, the precise role of lipid metabolism in uveitis pathogenesis is not clear. In our study, we analyzed the single-cell RNA-Seq (scRNA-Seq) data from cervical draining lymph nodes (CDLNs) of mice with experimental autoimmune uveitis (EAU), revealing an increased abundance of fatty acids in Th17 cells. Subsequent scRNA-Seq analysis identified the upregulation of DGAT1 expression in EAU and its marked reduction under various immunosuppressive agents. Suppression of DGAT1 prevented the conversion of fatty acids into neutral lipid droplets, resulting in the accumulation of lipid peroxidation and subsequent reduction in the proportion of Th17 cells. Inhibiting lipid peroxidation by Ferrostatin-1 effectively restored Th17 cell numbers that were decreased by DGAT1 inhibitor. Moreover, we validated the upregulation of DGAT1 in CD4+ T cells from patients with Vogt-Koyanagi-Harada (VKH) disease, a human uveitis. Inhibiting DGAT1 induced lipid peroxidation in human CD4+ T cells and reduced the proportion of Th17 cells. Collectively, our study focused on elucidating the regulatory mechanisms underlying Th17 cell survival and proposed that targeting DGAT1 may hold promise as a therapeutic approach for uveitis.
Authors
Tianfu Wang, Runping Duan, Zhaohuai Li, Bowen Zhang, Qi Jiang, Loujing Jiang, Jianjie Lv, Wenru Su, Lei Feng
Abstract
Using transcriptomic profiling at single-cell resolution, we investigated cell-intrinsic and cell-extrinsic signatures associated with pathogenesis and inflammation-driven fibrosis in both adult and pediatric patients with localized scleroderma (LS). We performed single-cell RNA-Seq on adult and pediatric patients with LS and healthy controls. We then analyzed the single-cell RNA-Seq data using an interpretable factor analysis machine learning framework, significant latent factor interaction discovery and exploration (SLIDE), which moves beyond predictive biomarkers to infer latent factors underlying LS pathophysiology. SLIDE is a recently developed latent factor regression-based framework that comes with rigorous statistical guarantees regarding identifiability of the latent factors, corresponding inference, and FDR control. We found distinct differences in the characteristics and complexity in the molecular signatures between adult and pediatric LS. SLIDE identified cell type–specific determinants of LS associated with age and severity and revealed insights into signaling mechanisms shared between LS and systemic sclerosis (SSc), as well as differences in onset of the disease in the pediatric compared with adult population. Our analyses recapitulate known drivers of LS pathology and identify cellular signaling modules that stratify LS subtypes and define a shared signaling axis with SSc.
Authors
Aaron BI Rosen, Anwesha Sanyal, Theresa Hutchins, Giffin Werner, Jacob S. Berkowitz, Tracy Tabib, Robert Lafyatis, Heidi Jacobe, Jishnu Das, Kathryn S. Torok
Abstract
Managing immune-related adverse events (irAEs) caused by cancer immunotherapy is essential for developing effective and safer therapies. However, cellular mechanism(s) underlying organ toxicity during anti-PD-(L)1 therapy remain unclear. Here, we investigated the effect of chronological aging on anti-PD-(L)1 therapy-induced irAE-like lung toxicity, utilizing tumor-bearing aged mice. Anti-PD-(L)1 therapy facilitated ectopic infiltration of T and B cells, and antibody deposition in lung of aged but not young mice. Adoptive transfer of aged lung-derived CD4 T cells into TCR-deficient mice revealed that both pathogenic CD4 T cells and aged host environment were necessary for the irAE-inducible responses. Single-cell transcriptomics of lung-infiltrating cells in aged mice demonstrated that anti-PD-(L)1 therapy elicited ICOS+CD4 T-cell activation. Disruption of ICOS-ICOSL interaction attenuated germinal center B-cell differentiation and subsequent lung damage, which were overcome by local administration of IL-21 in the lung of anti-PD-1 therapy-treated aged mice. Therefore, ICOS+CD4 T cells elicited under aged environment exacerbated aberrant immune responses and the subsequent lung dysfunction. Consistent with the findings from mouse model, ICOS up-regulation in CD4 T cells was associated with later irAE incidence in patients with cancer. These finding will help development of useful strategies for irAE management in cancer patients, many of whom are elderly.
Authors
Mari Yokoi, Kosaku Murakami, Tomonori Yaguchi, Kenji Chamoto, Hiroaki Ozasa, Hironori Yoshida, Mirei Shirakashi, Katsuhiro Ito, Yoshihiro Komohara, Yukio Fujiwara, Hiromu Yano, Tatsuya Ogimoto, Daiki Hira, Tomohiro Terada, Toyohiro Hirai, Hirotake Tsukamoto
Abstract
Skin inflammation in juvenile dermatomyositis (JDM) can signal disease onset or flare, and the persistence of cutaneous disease can prevent complete disease remission. The non-invasive study of cutaneous expression signatures through tape stripping (TS) holds the potential to reveal mechanisms underlying disease heterogeneity and organ-specific inflammation. The objectives of this study were to 1) define TS expression signatures in lesional and non-lesional JDM skin, 2) analyze TS signatures to identify JDM disease endotypes and 3) compare TS and blood signatures. While JDM lesional skin demonstrated interferon signaling as the top upregulated pathway, non-lesional skin uniquely highlighted pathways involved in metabolism, angiogenesis and calcium signaling. Both lesional and non-lesional skin shared inflammasome pathway dysregulation. Using unsupervised clustering of skin expression data, we identified a treatment-refractory JDM subgroup distinguished by upregulation of genes associated with mitochondrial dysfunction. The treatment-refractory JDM subgroup also demonstrated higher interferon, angiogenesis and innate immune expression scores in skin and blood, although scores were more pronounced in skin as compared to blood. Tape-stripping expression signatures in JDM provided insight into disease mechanisms and molecular subgroups. Skin, as compared to blood, transcriptional profiles served as more sensitive markers to classify disease subgroups and identify candidate treatment targets.
Authors
Jessica L. Turnier, Sarah M.H. Vandenbergen, Madison E. McClune, Christine Goudsmit, Sophia Matossian, Meredith Riebschleger, Nadine Saad, Jacqueline A. Madison, Smriti Mohan, Johann E. Gudjonsson, Lam C. Tsoi, Celine C. Berthier, J. Michelle Kahlenberg
Abstract
Systemic lupus erythematosus (SLE), an autoimmune disease, can cause psychiatric disorders, particularly depression, via immune activation. Human umbilical cord mesenchymal stromal cell (hUCMSC) transplantation (MSCT) has been shown to ameliorate immune dysfunction in SLE by inducing immune tolerance. However, whether MSCT can relieve the depressive symptoms in SLE remains incompletely understood. Here, we demonstrate that MSCT relieved early-onset depression-like behavior in both genetic lupus-prone (MRL/lpr) and pristane-induced lupus mice by rescuing impaired hippocampal synaptic connectivity. Transplanted hUCMSCs targeted Th1 cell-derived IFNγ to inhibit neuronal JAK-STAT1 signaling and downstream CCL8 expression, reducing phagocytic microglia apposition to alleviate synaptic engulfment and neurological dysfunction in young (8-week-old) lupus mice. Systemic delivery of exogenous IFNγ blunted MSCT-mediated alleviation of synaptic loss and depressive behavior in lupus mice, suggesting that the IFNγ-CCL8 axis may be an effective therapeutic target and that MSCT is a potential therapy for lupus-related depression. In summary, transplanted hUCMSCs can target systemic immunity to ameliorate psychiatric disorders by rescuing synaptic loss, highlighting the active role of neurons as intermediaries between systemic immunity and microglia in this process.
Authors
Han Xiaojuan, Dandan Wang, Liang Chen, Hua Song, Xiulan Zheng, Xin Zhang, Shengnan Zhao, Jun Liang, Tianshu Xu, Zhibin Hu, Lingyun Sun
Abstract
HLA-DR genes are associated with the progression from stage 1 and stage 2 to onset of stage 3 type 1 diabetes (T1D), after accounting HLA-DQ genes with which they are in high linkage-disequilibrium. Based on an integrated cohort of participants from two completed clinical trials, this investigation finds that sharing a haplotype with the DRB1*03:01 (DR3) allele, DRB3*01:01:02 and *02:02:01 have respectively negative and positive associations with the progression. Further, we uncovered two residues (β11, β26, participating in pockets 6 and 4, respectively) on the DRB3 molecule responsible for the progression among DR3 carriers, i.e. motif RY and LF respectively delay and promote the progression (Hazard Ratio = 0.73 and 2.38, p-value = 0.039 and 0.017, respectively). Two anchoring pockets 6 and 4 probably bind differential autoantigenic epitopes. We further investigated the progression association with the motifs RY and LF among carriers of DR3 and found that carriers of the motif LF have significantly faster progression than carriers of RY (HR = 1.48 and p = 0.019 in unadjusted analysis; HR = 1.39, p = 0.047 in adjusted analysis). New insights provide an impetus to examine the possible role of specific DRB3-binding peptides in the progression to T1D.
Authors
Lue Ping Zhao, George K. Papadopoulos, Jay S. Skyler, William W. Kwok, George P. Bondinas, Antonis K. Moustakas, Ruihan Wang, Chul-Woo Pyo, Wyatt C. Nelson, Daniel E. Geraghty, Åke Lernmark
Abstract
Type 1 diabetes (T1D) is precipitated by the autoimmune destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans. Chemokines have been identified as major conductors of islet infiltration by autoaggressive leukocytes, including antigen-presenting cells and islet autoantigen-specific T cells. We have previously generated a roadmap of gene expression in the islet microenvironment during T1D in a mouse model and found that most of the chemokine axes are chronically upregulated during T1D. The XCL1/XCR1 chemokine axis is of particular interest, since XCR1 is exclusively expressed on conventional dendritic cells type 1 (cDC1) that excel by their high capacity for T cell activation. Here we demonstrate cDC1 expressing XCR1 are present in and around the islets of patients with T1D and of islet-autoantibody positive individuals. Further, we show that XCL1 plays an important role in the attraction of highly potent dendritic cells expressing XCR1 to the islets in an inducible mouse model for T1D. XCL1-deficient mice display a diminished infiltration of XCR1+ cDC1 and subsequently a reduced magnitude and activity of islet autoantigen-specific T cells resulting in a profound decrease in T1D incidence. Interference with the XCL1/XCR1 chemokine axis might constitute a novel therapy for T1D.
Authors
Camilla Tondello, Christine Bender, Gregory J. Golden, Deborah Puppe, Elisa Blickberndt, Monika Bayer, Giulia K. Buchmann, Josef Pfeilschifter, Malte Bachmann, Edith Hintermann, Ralf P. Brandes, Michael R. Betts, Richard A. Kroczek, Urs Christen
Abstract
The mechanisms utilized by differentiating B cells to withstand highly damaging conditions generated during severe infections, like the massive hemolysis that accompanies malaria, are poorly understood. Here we demonstrate that ROCK1 regulates B cells differentiation in hostile environments replete with PAMPs (pathogen-associated molecular patterns) and high levels of heme by controlling two key heme-regulated molecules, BACH2 and Heme-regulated eIF2a kinase (HRI). ROCK1 phosphorylates BACH2 and protects it from heme-driven degradation. As B cells differentiate, furthermore, ROCK1 restrains their proinflammatory potential and helps them handle the heightened stress imparted by the presence of PAMPs and heme by controlling HRI, a key regulator of the integrated stress response and cytosolic proteotoxicity. ROCK1 controls the interplay of HRI with HSP90 and limits the recruitment of HRI and HSP90 to unique p62/SQSTM1 complexes that also contain critical kinases like mTORC1 and TBK1, and proteins involved in RNA metabolism, oxidative damage, and proteostasis like TDP-43. Thus, ROCK1 helps B cells cope with intense pathogen-driven destruction by coordinating the activity of key controllers of B cell differentiation and stress responses. These ROCK1-dependent mechanisms may be widely employed by cells to handle severe environmental stresses, and these findings may be relevant for immune-mediated and age-related neurodegenerative disorders.
Authors
Juan Rivera-Correa, Sanjay Gupta, Edd Ricker, Danny Flores-Castro, Daniel Jenkins, Stephen Vulcano, Swati P. Phalke, Tania Pannellini, Matthew M. Miele, Zhuoning Li, Nahuel Zamponi, Young-Bum Kim, Yurii Chinenov, Eugenia Giannopoulou, Leandro Cerchietti, Alessandra B. Pernis
Abstract
Autoimmune uveitis (AU) is a sight-threatening ocular autoimmune disorder that often manifests as retinal vasculitis. Increased neutrophil infiltration around retinal vessels has been reported during the progression of AU, while how they function is not fully recognized. Neutrophil extracellular traps (NETs), produced by activated neutrophils, have been suggested to be detrimental in autoimmune diseases. Here, we found that NETs were elevated in patients with active AU, and this was verified in an experimental AU (EAU) mouse model. Depletion of neutrophils or degradation of NETs with deoxyribonuclease-I (DNase I) could decrease CD4+ effector T cell (Teff) infiltration in retina and spleen to alleviate EAU. Moreover, we found that the expression of adhesion molecules, selectin, and antigen-presenting molecules was elevated in EAU retina and in retinal microvascular endothelial cells (RMECs) cocultured with NETs. The stimulated RMECs further facilitated CD4+ T cell adhesion, activation, and differentiation into Teffs. Mechanistically, NETs trigger RMEC activation by hastening cell senescence through the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. Slowing down senescence or inhibiting the cGAS/STING pathway in RMECs reduces the activation and differentiation of CD4+ T cells. These results suggest a deleterious role of NETs in AU. Targeting NETs would offer an effective therapeutic method.
Authors
Zuoyi Li, Zhuang Li, Yunwei Hu, Yanyan Xie, Yuxun Shi, Guanyu Chen, Jun Huang, Zhiqiang Xiao, Wenjie Zhu, Haixiang Huang, Minzhen Wang, Jianping Chen, Xiaoqing Chen, Dan Liang
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